2-alkyl-5,5-dimethyl-delta 2-4-thiazolinecarboxylic acids and process for preparing the same



' Patented July 26, 1949\ PATENT OFFICE z-aLxrn-as mmErnYL-m -r-- 'rnmzoiin\mcaaaoxmc ACIDS AND raoccss FOR PREPARING THE SAME John C. Sheehan, Railway, Ralph Mozingo, Elizabeth, Karl Folkers, Plainfield, and Max Tishler, Railway, N. 1., asslgnors to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application March 22, 1946,

Serial No. 656,512 7 4 Claim; (Cl. 260302) This invention relates to the preparation of dlpenicillamine and related compounds which are useful as intermediates in the synthesis of penicillin and chemically related substances having antibiotic activity, and particularly to processes for preparing such compounds from new intermediates obtained from readily available starting materials such as dl-valine and dimethylacrylic acid.

d-Penicillamine has been prepared from penicillin by hydrolyzing a salt of penicillin with hot dilute mineral acid (Nature 151, 107 (January 23, 1943)). It has been determined that the product thus obtained is an a-amino acid of the d or "unnaturaP series having a structure fully defined by the chemical names d-a-amino-fimercaptoisovaleric acid or d 5,3 dimethyl cysteine.

It is now discovered, in accordance with the I present invention, that penicillamine can be prepared readily and in good yield from certain new intermediate compounds such as 2-alkyl-4-isopropylidene-5(4)-oxazolones, their hydration products a-acyla'mino-fi,p-dimethylacrylic acids, and esters thereof, by reacting such a compound with absolute methanol saturated with hydrogen sulfide, and preferably containing dissolved sodium methoxide, neutralizing the reaction mixture with anhydrous mineral acid, removing the solvent under reduced pre ure, hydrating the 2-aJkyI-Sj-dimethyl-A I-th zoline carboxylic acid or ester thus formed to N-acyl-dl-penicillamine or an ester thereof, and converting the same to a dl-penicillamine hydrohalide and to free dl-penicillamine by reacting with aqueous hydrohaiic acid and then reacting the hydrohalide, under anhydrous conditions, with Pyridine.

The starting materials can be prepared from dl-valine by converting the same to an N-a- ,haloacyl derivative, forming a salt or addition compound of the N-a-haloacyl derivative with a nitrogenous heterocyclic compound having a pyridine nucleus, and converting the same to a 2-alkyl-4-isopropylidene-5(4)-oxazolone or to hydration products such as a a-acylamino-pL sdimethylacrylic acid and esters thereof in accordance with a procedure fully disclosed in a co-pending joint application of two of the present applicants, Mozingo, Folkers and Easton, Serial No. 656,511, filed March 22, 1946.

An alternate procedure for preparing said hydration products, by reacting dimethylacrylic acid with mercuric acetate, treating the addition product thus formed with a brominating agent and then with aqueous ammonium hydroxide to form a-amino-B-methoxyisovaleric acid, react ing the same with an acyl anhydride to formsacylamino-fi,fl-dimethylacrylic acid,.'is disclosed 5 in a co-pending joint application of two of the present applicants, Mozingo and Folkers, Serial No. 656,510 filed March 22, 1946, Patent Number 2,460,708.

It is also discovered, in accordance with the present invention that 2-methyl-4-isopropylidene-5(4)-oxazolone can be prepared by reactin'g a-amino-B-methoxyisovaleric acid with acetic anhydride and triethyl amine andremoving solvents from the reaction mixture under reduced pressure as more fully hereinafter disclosed.

In carrying out the process of the present invention, a 2-a1kyl-4-isopropylidene-5(4)-oxazolone or a corresponding hydration product, prepared by any of the procedures outlined above,

is dissolved in absolute methanol and added slowly to absolute methanol saturated at about 0 C. with hydrogen sulfide. It is also advantageous, though not absolutely necessary, that the methanol-hydrogen sulfide solution contain dissolved sodium methoxide. Durin the addition,

4-thiazolinecarboxylic acid or ester thereof.

This can be purified by dissolving in ether and quickly filtering to remove sodium chloride. Upon standing, the product crystallizes from the ether filtrate and can be further purified by recrystallization from benzene. The thiazoline is quantitatively converted to N-acyl-dl-penicillamine by warming with water.

In carrying out the process to prepare dl-penicillamine and related compounds, it is not nec- 5 essary to isolate the thiazoline compound, The

crude mixture obtained after neutralization and evaporation of solvent as above described can be merely warmed with water and chilled to cause crystallization of the N-acyl-dl-penicillamine,

which is recovered by filtration. The N-acyldl-penicillamine is purified by recrystallization from hot water.

- N-acyl-dl-penicillamine is converted to dlpenicillamine, preferably through a hydrohalide of dl-penicillamine, by reacting with an aqueous hydrohalic acid in an oxygen-tree (nltrogeni through the solution, the temperature being atmosphere. as by refluxing with hydrochloric aradually increased to 25. acid for about sixteen hours, concentrating and After neutralization with 2.2 mi. of methanol drying the reaction mixture. and crystailizing containing 0.463. or dry "hydrogen chloride per the dl-penicillaminc hydrchaiide by trituration g ml., the solvent was removed (40) under reduced with dry ether. When the hydrohalide is dispressure. The residual amber syrup was dissolved in absolute methanol, treated with pyr-' solved in dry ether and quickly filtered from idine, and the reaction mixture is then cooled sodium chloride. The filtrate soon crystallized, to about C., dl-penicillamine crystallizes, out yielding 7.2 g. of colorless needles, M. P. l26-130. andisrecovered by filtration. By recrystallization from benzene the melting The following is a graphic representation of point was raised to 130-132. This product, 2,5,5- the procedure above described using as a starting trimethyl-M-d-thiazolinecarboxylic acid, coninaterial B-methyl-i-isopropylidene-itQ-oxasctains sulfur, gives a negative ferric chloride test Jone; for the sulfhydryl group, and dissolves in a OH on. 0 sodium bicarbonate solution with efiervescence.

l Analysis: A

f- Calculated for mmioms: c, 48.53; a, 6.40; c N HsB+NaOOK| C a NH 0H N 397 "22" =8 Found: 0,413.81; n, 6.10; 11.7.91.

E (3m This thiazoline is rapidly and quantitatively R converted to N-acetyl-dl-peniclllamine by warm- W335 rio I :13 ing in water for several minutes. o 0 cm 0 26 Example III mo K A solution of the crude azlactone, prepared {A from 73.5 g. of a-amin'o-B-methoxyisovaleric acid 0 I E NH 4 on C on as in Example I, in 85 ml. of methanol was added 0 in one and one-half hours to a solution of 1.77 g. i 5 80 of sodium in 292 ml. of methanol saturated with hydrogen sulfide at 0. A stream of hydrogen ggfiiflfi xgfi m ggfifi? sulfide was allowed to pass through the solution (N-acetyl-dl-pcnicillamine) during the addition and for sixteen hours there- Aqueous hydroafter, thetemperature gradually being increased chloric acid to 25. After neutralization with 6.3 ml. of methanol containing 0.43 g. of hydrogen chloride c 0 CH: per ml., the solvent was removed under reduced 1E? pressure. The amber syrup was warmed (90) with 200 ml. of water for ten minutes, then chilled l anhydrous l C(igfi on CgAH on and filtered, yielding 75.5 g. (80% overall) of 1501 N-acetyl penicillamine; M. P. 175-177 (dec.). dMmmoMnempw. dl- -gmmoflqne mptol This product, when recrystallized from hot mvmm g gr'fgg r. was recovered as glistening colorless ed ififii f needles melting at 183 0,

The following examples illustrate methods of Analysis: carrying out the present invention, but it will be calculated for c'lHmotNsi C, 5; understood that these examples are given by way N. 7. 33. of illustration and not of limitation. Found- 4 7, H, 6.98; N, 7.08.

Example I an x mpl IV A mixture of 735 f m A mixture of 20 g. of recrystallized N-acetyl isovaleric acid, 180 ml. of acetic anhydride, and l mine. 210 ml. of 2.5 N hy rochloric 1 ml. of triethylamine was w rm an steam acid and 105 ml. of water was refluxed sixteen bath f r 01194131; n Aft r removal of sob hours under nitrogen. A trace of hydrogen su]- vents under reduced pressure, t residue t 66 flde was evolved. After concentration under relized as crude 2-methyl-4-isopropylidene-5(4)- duced PFQSSm'ei the syrup was dried by u hi oxazolone. The product is suitable for use withtwice Wlth absolute alcohol and n e with. benout further purification. Upon recrystallization under Reduced Pressma- The r sidue crysfrom 3040s petroleum ether. 635 g. (94%) of tallized readily on trituration with dry ether, the azlactone was recovered having a melting yielding (100%) Of -l ioillamine bypoint of 37-38 C. A sample was evaporatively dmcmm'ldei 145-143 (dam), The p y distilled at c and 0 01 mm and analyzed imas determined by iodine titration was 96-98%,

mediateiy. Example V i Calculated tor 01W: d. 60. H. 1 as A solution or the aforementioned penicillalnino Found: C, 60.34; H, 8.21. hydrochloride (18.6 g.) in 28 ml. or absolute alco- I Pu n hol was clarified by centrifuging. After the additlon or 15 ml. of pyridine and cooling to 0', (11- A solution or 0.8 I. oi sodium in 100 mi. oi abpenicillamine was filtered 01!, weight 9.70 g.

solute methanol was saturated at 0 with 111- 1'0 (65%): M. P. 201-202 (dec.). undepressed with drogen suliide. Over a period or one hour, a authentic penicillamine. The nitrate was consolution or 2-methyl-4-isopropylideno-5(4)- 0X- centrated to a syrup, dissolved in 15 ml. of water asolone in 40 m1. of methanol was added. Dining and made alkaline with 30% sodium hydroxide. the addition and for sixteen hours thereafter, a Alter concentration under reduced pressure, the stream of hydrogen sulfide was allowed to pass 15 last traces of. pyridine were removed with ether.

The mixture was acidified with hydrochloric acid, concentrated to dryness, flushed with absolute alcohol and dissolved in absolute alcohol. Subsequent removal of sodium chloride and neutralization as before with pyridine afforded an additional 1.66 g. of penicillamine; M. P. 201 (dec.). The total yield overall from N-acetyl penicillamine was 77%.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and our invention is to be limited only bythe appended claims.

We claim:

1. The process that comprises reacting a 2- iower alkyl-4-isopropylidene-5(4) -oxazolone with an absolute methanol solution of sodium saturated with hydrogen sulfide, neutralizing the reaction mixture with anhydrous mineral acid, evaporating the solvent under reduced pressure, dissolving the residue in dry ether, filtering, and crystallizing from the filtrate the corresponding 2-lower alkyl 5,5 dimethyl-AA-thiazoiine carboxylic acid.

2. The process that comprises reacting 2- methyl-4-isopropylidene-5(4) -oxazolone with an absolute methanol solution or sodium saturated with hydrogen sulfide, neutralizing the reaction mixture with anhydrous hydrogen chloride. evaporating the solvent under reduced pressure, dissolving the residue in dry ether, filtering, and crystallizing from the filtrate 2,5,5-trimethyl- A -4-thiazolinecarboxylic acid.

3. A 2-lower alkyl-5,5-dimethyl-A'-4-thiazoline carboxylic acid.

4. 2,5,5-trimethyi A 4-thlazolinecarboxylic acid.

JOHN C. SHEEHAN. RALPH MOZINGO. KARL FOLKERS. MAX TISHLER.

. 6 REFERENCES CITED The following references are oi record in the file of this patent:

UNITED STATES PATENTS Number Name Date 743,986 Nicolaier et al Nov. 10. 1903 2,375,885 Babcock May 15, 1945 2,391,993 Mathes Jan. 1, 1946 OTHER REFERENCES Carter: J. Biol. Chem., vol. 139 (1941), pp. 247-254. I

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